Methods of treating developmental disorders and/or seizure disorders with etifoxine

ABSTRACT

Methods of treating developmental disorders and/or seizure disorders with etifoxine, a deuterated analog of etifoxine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided. The methods provide therapeutic compositions that may be used to improve one or more symptoms of the developmental disorder and/or seizure disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of and priority to U.S. ProvisionalApplication No. 62/563,155, filed Sep. 26, 2017, which is incorporatedby reference in its entirety.

TECHNICAL FIELD

Methods of treating developmental disorders and/or seizure disorderswith etifoxine are provided.

BACKGROUND

Treatments for developmental disorders such as Autistic SpectrumDisorder, Dravet syndrome, Rett syndrome, Angelman syndrome, Fragile Xsyndrome, and Fragile X-associated tremor/ataxia syndrome are limited.Angelman syndrome is a neurodevelopmental disorder caused by loss offunction of the UBE3A gene encoding a ubiquitin E3 ligase. Motordysfunction is a characteristic feature of Angelman syndrome, butneither the mechanisms of action nor effective therapeutic strategieshave yet been elucidated.

Fragile X syndrome may be the most common genetic cause of intellectualdisability and the most common single-gene cause of autism. It is causedby mutations on the fragile X mental retardation gene (FMR1) and lack offragile X mental retardation protein, which in turn, leads to decreasedinhibition of translation of many synaptic proteins. The main effortshave focused on metabotropic glutamate receptor (mGluR) targetedtreatments; however, investigation on the gamma-aminobutyric acid (GABA)system and its potential as a targeted treatment is less emphasized. Thefragile X mouse models (Fmr1-knock out) show decreased GABA subunitreceptors, decreased synthesis of GABA, increased catabolism of GABA,and overall decreased GABAergic input in many regions of the brain.These symptoms are also observed in individuals with autism and otherneurodevelopmental disorders, therefore the targeted treatments forFragile X syndrome are leading the way in the treatment of otherneurodevelopmental syndromes and autism. Potential GABAergic treatments,such as riluzole, gaboxadol, tiagabine, and vigabatrin have beendiscussed. However, further studies are needed to determine the safetyand efficacy of GABAergic treatments for Fragile X syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onsetdisorder, usually occurring after age 50. Mutations in the FMR1 geneincrease the risk of developing FXTAS. The mutation relates to a DNAsegment known as a CGG triplet repeat which is expanded within the FMR1gene. Normally, this DNA segment is repeated from 5 to about 40 times.In people with FXTAS the CGG segment may be repeated 55 to 200 times.This mutation is known as an FMR1 gene premutation. An expansion of morethan 200 repeats, a full mutation, causes Fragile X syndrome discussedabove. FXTAS is typically characterized by problems with movement andthinking ability (cognition). FXTAS signs and symptoms usually worsenwith age. Affected individuals have areas of damage in the cerebellum,the area of the brain that controls movement. Characteristic features ofFXTAS are intention tremor, which is trembling or shaking of a limb whentrying to perform a voluntary movement such as reaching for an object,and problems with coordination and balance (ataxia). Many affectedindividuals develop other movement problems, such as parkinsonism, whichincludes tremors when not moving (resting tremor), rigidity, andunusually slow movement (bradykinesia). In addition, affectedindividuals may have reduced sensation, numbness or tingling, pain, ormuscle weakness in the lower limbs, and inability to control the bladderor bowel. Other symptoms may include chronic pain syndromes, such asfibromyalgia and chronic migraine, hypothyroidism, hypertension,insomnia, sleep apnea, vertigo, olfactory dysfunction, and hearing loss.People with FXTAS commonly have cognitive disabilities such asshort-term memory loss and loss of executive function, which is theability to plan and implement actions and develop problem-solvingstrategies. Loss of this function impairs skills such as impulsecontrol, self-monitoring, focusing attention appropriately, andcognitive flexibility. Many people with FXTAS experience psychiatricsymptoms such as anxiety, depression, moodiness, or irritability.

There is currently no targeted therapeutic intervention that can arrestor reverse the pathogenesis of FXTAS. However a number of treatmentapproaches of potential symptomatic benefit have been suggested.Primidone, beta-blockers such as propanolol, topiramate,carbidopa/levodopa, and benzodiazepines have been suggested to controltremors associated with FXTAS; botulinum toxin for involuntary muscleactivities, such as dystonia and spasticity; carbidopa/levodopa,amantadine and buspirone for ataxia; cholinesterase inhibitors such asdonepezil, and memantine (an NMDA antagonist) for cognitive deficits anddementia; and antidepressants and antipsychotics for psychiatricsymptoms. See, e.g., Hagerman, et al., Clin Intery Aging. 2008 June; 3(2): 251-262.

Rett syndrome is a neurodevelopmental disorder that typically affectsgirls. It is characterized by normal early growth and developmentfollowed by a slowing of development, loss of purposeful use of thehands, distinctive hand movements, slowed brain and head growth,problems with walking, seizures, and intellectual disability. Nearly allcases of Rett syndrome are caused by a mutation in the methyl CpGbinding protein 2, or MECP2 gene. The MECP2 gene contains instructionsfor the synthesis of methyl cytosine binding protein 2 (MeCP2), which isutilized in brain development and acts as one of the many biochemicalswitches that can either increase or decrease gene expression. The maindiagnostic criteria or symptoms include partial or complete loss ofacquired purposeful hand skills, partial or complete loss of acquiredspoken language, repetitive hand movements (such has hand wringing orsqueezing, clapping or rubbing), and gait abnormalities, includingtoe-walking or an unsteady, wide-based, stiff-legged walk. Supportivecriteria are not required for a diagnosis of Rett syndrome but may occurin some individuals. In addition, these symptoms, which vary in severityfrom child to child, may not be observed in very young children but maydevelop with age. A child with supportive criteria but none of theessential criteria does not have Rett syndrome. Supportive criteriainclude scoliosis, teeth-grinding, small cold hands and feet in relationto height, abnormal sleep patterns, abnormal muscle tone, heartabnormalities, inappropriate laughing or screaming, intense eyecommunication, and diminished response to pain.

There is no cure for Rett syndrome. Treatment for the disorder issymptomatic, focusing on the management of symptoms, and supportive,requiring a multidisciplinary approach. Medication may be needed forbreathing irregularities and motor difficulties, and anticonvulsantdrugs may be used to control seizures.

Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy(SMEI) is a severe form of intractable epilepsy that begins in infancywith febrile seizures. Later, patients also manifest other seizuretypes, including absence, myoclonic, and partial seizures. The EEG isoften normal at first, but later characteristically shows generalizedspike-wave activity. Psychomotor development stagnates around the secondyear of life, and affected individuals show subsequent mental declineand other neurologic manifestations. Dravet syndrome is associated withataxia, slowed psychomotor development, and mental decline, and is oftenrefractory to medication. Dravet syndrome has been associated withmutation of the SCN1A gene on chromosome 2q24.

Accordingly, there remains a need for effective treatments of patientswith developmental disorders, such as Autistic Spectrum Disorder,pervasive developmental disorder, Autism, Angelman syndrome, Fragile Xsyndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), Rettsyndrome, Asperger's syndrome, Childhood Disintegrative Disorder,Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi Syndrome,Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, TardiveDyskinesia, Williams Syndrome and/or seizure disorders per se, and/orseizure disorders associated with any of the foregoing developmentaldisorders.

Seizure disorders typically involve abnormal nerve cell activity in thebrain, causing seizures which may be manifested by periods of unusualbehavior, sensations, diminished consciousness and sometimes loss ofconsciousness. Seizures can be a symptom of many different disordersthat can affect the brain. Epilepsy is a seizure disorder characterizedby recurrent seizures. See, e.g., Blume et al., Epilepsia. 2001;42:1212-1218. Epileptic seizures are usually marked by abnormalelectrical discharges in the brain and typically manifested by suddenbrief episodes of altered or diminished consciousness, or involuntarymovements. Non-epileptic seizures may or may not be accompanied byabnormal electrical activity in the brain and may be caused bypsychological issues or stress. Drug or alcohol withdrawal can alsocause seizures. Seizure symptoms can vary widely. Some seizures canhardly be noticed, while others are totally disabling. Seizure disordersinclude epilepsy.

Medications are used to treat seizure disorders and can be referred toas anti-epileptic drugs (“AED”). The treatment of recurrent seizurespredominantly centers on the utilization of at least one AED, withpossible adjunctive use of a second or even third agent in the case ofmonotherapeutic failure. See, Tolman and Faulkner, Ther Clin Risk Manag.2011; 7: 367-375. However, approximately 30%-40% of epileptic patientshave inadequate seizure control with just one AED, and require the useof adjunctive agents. Id. A subset of this group will have regular andpersistent seizure activity despite reasonable doses of multiple AEDs.These seizures are considered refractory to treatment. Id. Accordingly,there remains a need for improved and/or additional therapies fortreating seizure disorders.

SUMMARY

Methods of treating a developmental disorder described herein includeadministering at least one compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof to provideimprovement in one or more symptoms of the developmental disorder. Inembodiments, methods of treating a developmental disorder describedherein include administering at least one etifoxine selected fromR-etifoxine, S-etifoxine, and combinations thereof. In embodiments,methods of treating a developmental disorder described herein includeadministering at least one deuterated analog of etifoxine of formula Ibelow:

including pharmaceutically acceptable salts, wherein each X¹, X², X³ areindependently selected from the group consisting of hydrogen anddeuterium. In embodiments, the deuterated analog of etifoxine isselected from deuterated R-etifoxine, deuterated S-etifoxine, andcombinations thereof.

In embodiments, methods of treating a developmental disorder describedherein include administering at least one compound selected from thegroup consisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt thereof to a patient in need thereof toprovide improvement in next day functioning of the patient. Inembodiments, methods of treating a developmental disorder describedherein include administering at least one etifoxine selected fromR-etifoxine, S-etifoxine, and combinations thereof. In embodiments,methods of treating a developmental disorder described herein includeadministering at least one deuterated analog of etifoxine of formula Ibelow:

including pharmaceutically acceptable salts, wherein each X¹, X², X³ areindependently selected from the group consisting of hydrogen anddeuterium. In embodiments, the deuterated analog of etifoxine isselected from deuterated R-etifoxine, deuterated S-etifoxine, andcombinations thereof.

In embodiments, the developmental disorder may be an Autistic SpectrumDisorder, pervasive developmental disorder, Autism, Angelman syndrome,Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS),Rett syndrome, Asperger's syndrome, Childhood Disintegrative Disorder,Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi Syndrome,Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, 22q11.2syndrome, Tardive Dyskinesia, Williams Syndrome and/or seizure disordersper se, and/or seizure disorders associated with any of the foregoingdevelopmental disorders. Examples of seizure disorders include epilepsy,epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonicabsences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-KleffnerSyndrome, Rasmussen's syndrome, Doose syndrome, CDKL5 disorder, Westsyndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtaharasyndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor,and acute repetitive seizures, benign rolandic epilepsy, statusepilepticus, refractory status, epilepticus, super-refractory statusepilepticus (SRSE), PCDH19 pediatric epilepsy, increased seizureactivity or breakthrough seizures (increased seizure activity: alsocalled serial or cluster seizures). Seizure disorders include sodiumchannel protein type 1 subunit alpha (Scn1a)-related disorders.

Methods of treating a seizure disorder are also provided and, inembodiments, include administering to a subject in need thereof at leastone compound selected from the group consisting of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable saltthereof.

In embodiments, methods of treating a seizure disorder includeadministering at least one compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt thereof to a subject in need thereof to provideimprovement in one or more symptoms of the seizure disorder. Inembodiments, methods of treating a seizure disorder described hereininclude administering at least one etifoxine selected from R-etifoxine,S-etifoxine, and combinations thereof. In embodiments, methods oftreating a seizure disorder described herein include administering atleast one deuterated analog of etifoxine of formula I below:

including pharmaceutically acceptable salts, wherein each X¹, X², X³ areindependently selected from the group consisting of hydrogen anddeuterium. In embodiments, the deuterated analog of etifoxine isselected from deuterated R-etifoxine, deuterated S-etifoxine, andcombinations thereof.

In embodiments, methods of treating a seizure disorder includeadministering at least one compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt thereof to a subject in need thereof to provideimprovement in next day functioning of the subject. In embodiments,methods of treating a seizure disorder described herein includeadministering at least one etifoxine selected from R-etifoxine,S-etifoxine, and combinations thereof. In embodiments, methods oftreating a seizure disorder described herein include administering atleast one deuterated analog of etifoxine of formula I below:

including pharmaceutically acceptable salts thereof, wherein each X¹,X², X³ are independently selected from the group consisting of hydrogenand deuterium. In embodiments, the deuterated analog of etifoxine isselected from deuterated R-etifoxine, deuterated S-etifoxine, andcombinations thereof.

In embodiments, the seizure disorders treated in accordance with thepresent disclosure include epilepsy, epilepsy with generalizedtonic-clonic seizures, epilepsy with myoclonic absences, frontal lobeepilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen'ssyndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder, infantilespasms (West syndrome), juvenile myoclonic epilepsy (JME),vaccine-related encephalopathy, intractable childhood epilepsy (ICE),Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5disorder, childhood absence epilepsy, essential tremor, acute repetitiveseizures, benign rolandic epilepsy, status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus (SRSE), PCDH19pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawalinduced seizures, increased seizure activity or breakthrough seizures(increased seizure activity; also called serial or cluster seizures).

Methods of treating a developmental encephalopathy are also providedand, in embodiments, include administering to a subject in need thereofat least one compound selected from the group consisting of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable saltthereof.

In embodiments, at least one of etifoxine, R-etifoxine, S-etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable saltthereof is administered to the subject from one to six times a day.Administration may be by any appropriate route, including oral, buccal,sublingual, rectal, topical, intranasal, vaginal, parenteral,combinations thereof, and the like.

DETAILED DESCRIPTION

Described herein are methods of treating a developmental disorder thatinclude administering at least one compound selected from the groupconsisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt thereof to a patient in need thereof toprovide improvement in one or more symptoms of the disorder. Inembodiments, methods of treating a developmental disorder describedherein include administering at least one compound selected from thegroup consisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt thereof to a patient in need thereof toprovide improvement in next day functioning of the patient. Describedherein are methods of treating a seizure disorder that includeadministering at least one compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt thereof to a patient in need thereof to provideimprovement in one or more symptoms of the disorder. In embodiments,methods of treating a seizure disorder described herein includeadministering at least one compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt thereof to a patient in need thereof to provideimprovement in next day functioning of the patient. In embodiments,methods of treating a developmental disorder and/or a seizure disorderinclude administering at least one compound selected from the groupconsisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt thereof to a patient in need thereof.In embodiments, methods of treating a developmental disorder and/or aseizure disorder include administering a pharmaceutical compositioncontaining at least one of etifoxine, a deuterated analog of etifoxine,or a pharmaceutically acceptable salt thereof to a patient in needthereof. In embodiments, methods of treating a developmental disorderand/or a seizure disorder include administering a pharmaceuticalcomposition containing at least one of etifoxine, a deuterated analog ofetifoxine, or a pharmaceutically acceptable salt thereof to a patient inneed thereof to provide improvement in one or more symptoms of thedisorder. In embodiments, methods of treating a developmental disorderand/or a seizure disorder described herein include administering apharmaceutical composition containing at least one of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable saltthereof to a patient in need thereof to provide improvement in next dayfunctioning of the patient.

In embodiments, the developmental disorder may be an Autistic SpectrumDisorder, pervasive developmental disorder, autism, Angelman syndrome,Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS),Rett syndrome, Asperger's syndrome, Childhood Disintegrative Disorder,Attention-deficit/hyperactivity disorder (ADHD), Prader-Willi Syndrome,Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, TardiveDyskinesia, 16p11.2 deletion syndrome, 16p11.2 recurrent microdeletion,Albright hereditary osteodystrophy, Alstrom syndrome, Bardet-Biedlsyndrome, Borjeson-Forssman-Lehmann syndrome, Cohen syndrome, Downsyndrome, Klinefelter syndrome, Turner syndrome, Smith-Magenis syndrome,21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia, 2q37Microdeletion syndrome, 3q29 Recurrent Deletion, Achondroplasia,ADNP-Related Intellectual Disability and melanocortin 4 receptor (MC4R)deficiency, Williams Syndrome and/or seizure disorders per se, and/orseizure disorders independent of, or associated with, any of theforegoing developmental disorders.

In embodiments, the developmental disorder is Angelman syndrome.

In embodiments, the developmental disorder is Fragile X syndrome.

In embodiments, the developmental disorder is Rett syndrome.

In embodiments, the development disorder is a developmentalencephalopathy. Some non-limiting examples include tuberous sclerosis,early myoclonic encephalopathy, and early-onset epilepticencephalopathy.

In embodiments, the developmental disorder is a developmentalencephalopathy associated with a genetic mutation of a one or more ofthe following genes: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2,CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2,EPM2A, FLNA, FOXG1 duplications, GABRA1, GABRB3, GABRG2, GLI3, GNAO1,GOSR2, GRIN1, GRIN2A, GRIN2B, GRIN2D, HCN1, HNRNPU, IER3IP1, IQSEC2,KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MAGI2,MEF2C, NEDDL4, NDP, NHLRC1, NRXN1, PCDH19, PIGA, PIGQ, PLCB1, PNKP,PNPO, PRICKLE1, PRICKLE2, PRRT2, PTEN, PURA, QARS, RELN, SCA2, SCARB2,SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SETBP1, SIAT9, SIK1, SLC12A5,SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2,ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TCF4 andWWOX encephalopathy. In embodiments, the developmental disorder is adevelopmental encephalopathy associated with a genetic mutation of theCDKL5 gene. In embodiments, the developmental disorder is adevelopmental encephalopathy associated with a genetic mutation of thePCDH19 gene.

In embodiments, the developmental disorder is a neurodevelopmentaldisorder. Some non-limiting examples of neurodevelopmental disordersinclude 22Q syndrome, such as 22q11.2 syndrome and/or 22q11.2duplication syndrome, DiGeorge syndrome (DGS), DiGeorge anomaly,velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome(CTAF), Opitz G/BBB syndrome, Cayler cardiofacial syndrome, Shprintzensyndrome, Takao syndrome, Sedlackova syndrome, Strong syndrome,congenital thymic aplasia, and thymic hypoplasia.

In embodiments, the developmental disorder is an intellectualdevelopmental disability (IDD), such as Autism Spectrum Disorder (ASD).In embodiments, the patient of the disclosed method has developmentalencephalopathy and an IDD or ASD disorder. Common IDD and ASD that arecomorbid with developmental encephalopathies include, but are notlimited to, fragile X syndrome (FXS), Rett syndrome (RTT), Angelmansyndrome, Prader-Willi syndrome, Velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, neuroligin mutations and“interneuronopathies” resulting from aristaless-related homeobox,X-linked (ARX) and Nueropilin 2 (NRP2) gene mutations.

In embodiments, the seizure disorder may include epilepsy, epilepsy withgeneralized tonic-clonic seizures, epilepsy with myoclonic absences,frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome,Rasmussen's syndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder,infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME),vaccine-related encephalopathy, intractable childhood epilepsy (ICE),Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5disorder, childhood absence epilepsy, essential tremor, acute repetitiveseizures, benign rolandic epilepsy, status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus (SRSE), PCDH19pediatric epilepsy, catastrophic epilepsy, increased seizure activity orbreakthrough seizures (also called serial or cluster seizures). Inembodiments, the seizure disorder is associated with a sodium channelprotein type 1 subunit alpha (Scn1a)-related disorder. Scn1a-relateddisorders include generalized epilepsy with febrile seizures plus,intractable childhood epilepsy with generalized tonic-clonic seizures,intractable infantile partial seizures, myoclonic-astatic epilepsy,severe myoclonic epilepsy in infancy, simple febrile seizures, Dravetsyndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, andvaccine-related encephalopathy and seizures.

In embodiments, the seizure disorder is status epilepticus (SE). SE ischaracterized by an epileptic seizure of greater than five minutes ormore than one seizure within a five-minute period without the personreturning to normal between them. SE can be a dangerous condition thatcan lead to mortality if treatment is delayed. SE can be convulsive,with a regular pattern of contraction and extension of the arms andlegs, or non-convulsive, with a change in a person's level ofconsciousness of relatively long duration but without large scalebending and extension of the limbs due to seizure activity. ConvulsiveSE (CSE) may be further classified into (a) tonic-clonic SE, (b) tonicSE, (c) clonic SE and (d) myoclonic SE. Non-convulsive SE (NCSE) ischaracterized by abnormal mental status, unresponsiveness, ocular motorabnormalities, persistent electrographic seizures, and possible responseto anticonvulsants.

In embodiments, the seizure disorder is a CDKL5 disorder.

In embodiments, the seizure disorder is a PCDH19 disorder.

In embodiments, the disorder is a combination of disorders. For example,the methods described herein may be used to treat both a developmentaldisorder and a seizure disorder.

Symptoms of developmental disorders and/or seizure disorders mayinclude, but are not limited to, episodes involving ataxia, gaitimpairment, speech impairment, vocalization, impaired cognition,abnormal motor activity, clinical seizure, subclinical seizure,hypotonia, hypertonia, drooling, and mouthing behavior, aura, repetitivemovements, and unusual sensations. In embodiments, the methods andcompositions described herein may reduce or prevent one or moredifferent symptoms related to the disorder.

Symptoms of a seizure disorder may include, but are not limited to,episodes involving ataxia, gait impairment, speech impairment,vocalization, impaired cognition, abnormal motor activity, clinicalseizure, subclinical seizure, hypotonia, hypertonia, drooling, andmouthing behavior, aura, repetitive movements, and unusual sensations.In embodiments, the methods and compositions provided may reduce orprevent one or more different types of seizures. Generally, a seizurecan include repetitive movements, unusual sensations, and combinationsthereof. Seizures can be categorized as focal seizures (also referred toas partial seizures) and generalized seizures. Focal seizures affectonly one side of the brain, while generalized seizures affect both sidesof the brain. Specific types of focal seizures include simple focalseizures, complex focal seizures, and secondarily generalized seizures.Simple focal seizures can be restricted or focused on a particular lobe(e.g., temporal lobe, frontal lobe, parietal lobe, or occipital lobe).Complex focal seizures generally affect a larger part of one hemispherethan simple focal seizures, but commonly originate in the temporal lobeor the frontal lobe. When a focal seizure spreads from one side(hemisphere) to both sides of the brain, the seizure is referred to as asecondarily generalized seizure. Specific types of generalized seizuresinclude absences (also referred to as petit mal seizures), tonicseizures, atonic seizures, myoclonic seizures, tonic clonic seizures(also referred to as grand mal seizures), and clonic seizures.

The methods of treatment described herein include administering at leastone compound selected from the group consisting of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof to a patient.

Etifoxine is a chiral molecule that has been used as a racemate.Etifoxine is 6-chloro-2-(ethylamino)4-methyl-4-phenyl-4H-3,1-benzoxazineand can be represented by the following chemical structure:

where * indicates the chiral center in the molecule.

Etifoxine hydrochloride is represented as:

U.S. Pat. No. 3,725,404 describes various methods of preparing and usingetifoxine as racemic mixture, the contents of which are herebyincorporated by reference in their entirety.

In embodiments, the compound includes at least one etifoxine directed tothe chemical structure represented below:

or a pharmaceutically acceptable salt, solvate, hydrate or prodrugthereof.

In embodiments, the compound includes at least one etifoxine directed tothe chemical structure represented below:

or a pharmaceutically acceptable salt, solvate, hydrate or prodrugthereof.

(+)-Etifoxine and/or R-etifoxine corresponds to the R enantiomer ofetifoxine. (−)-Etifoxine and/or S-etifoxine corresponds to the Senantiomer of etifoxine. In embodiments, the compound may be(+)-Etifoxine. In embodiments, the compound may be (−)-Etifoxine. Inembodiments, the at least one compound may include a combination ofR-efifoxine and S-etifoxine.

In embodiments, the compound is selected from enantiomerically pureR-etifoxine and pharmaceutically acceptable salts, solvates, hydratesand prodrugs thereof. In embodiments, the compound is selected fromenantiomerically pure R-etifoxine and pharmaceutically acceptable saltsthereof. In embodiments, the compound is R-etifoxine hydrochloride.

In embodiments, the enantiomerically pure R-etifoxine comprises at leastabout 80% by weight R-etifoxine and at most about 20% by weightS-etifoxine, at least about 90% by weight R-etifoxine and at most about10% by weight S-etifoxine, at least about 95% by weight R-etifoxine andat most about 5% by weight S-etifoxine, at least about 96.6% by weightR-etifoxine and at most about 3.4% by weight S-etifoxine, at least about97% by weight R-etifoxine and at most about 3% by weight S-etifoxine, atleast about 99% by weight R-etifoxine and at most about 1% by weightS-etifoxine or at least about 99.9% by weight R-etifoxine and at mostabout 0.1% by weight S-etifoxine. In one embodiment, the pureR-etifoxine comprises at least about 96.6% by weight R-etifoxine and atmost about 3.4% by weight S-etifoxine, at least about 97% by weightR-etifoxine and at most about 3% by weight S-etifoxine, at least about98% by weight R-etifoxine and at most about 2% by weight S-etifoxine orat least about 99% by weight R-etifoxine and at most about 1% by weightS-etifoxine. In embodiments, the weights are based upon total weight ofetifoxine.

In embodiments, the compound is selected from enantiomerically pureS-etifoxine and pharmaceutically acceptable salts, solvates, hydratesand prodrugs thereof. In embodiments, the compound is selected fromenantiomerically pure S-etifoxine and pharmaceutically acceptable saltsthereof. In embodiments, the compound is S-etifoxine hydrochloride.

In embodiments, the enantiomerically pure S-etifoxine comprises at leastabout 80% by weight S-etifoxine and at most about 20% by weightR-etifoxine, at least about 90% by weight S-etifoxine and at most about10% by weight R-etifoxine, at least about 95% by weight S-etifoxine andat most about 5% by weight R-etifoxine, at least about 96.6% by weightS-etifoxine and at most about 3.4% by weight R-etifoxine, at least about97% by weight S-etifoxine and at most about 3% by weight R-etifoxine, atleast about 99% by weight S-etifoxine and at most about 1% by weightR-etifoxine or at least about 99.9% by weight S-etifoxine and at mostabout 0.1% by weight R-etifoxine. In one embodiment, the pureS-etifoxine comprises at least about 96.6% by weight S-etifoxine and atmost about 3.4% by weight R-etifoxine, at least about 97% by weightS-etifoxine and at most about 3% by weight R-etifoxine, at least about98% by weight S-etifoxine and at most about 2% by weight R-etifoxine orat least about 99% by weight S-etifoxine and at most about 1% by weightR-etifoxine. In embodiments, the weights are based upon total weight ofetifoxine.

In embodiments, the compound is a deuterated analog of etifoxine. Inembodiments, the compound is a deuterated analog of R-etifoxine. Inembodiments, the compound is a deuterated analog of S-etifoxine.

In embodiments, the deuterated analog of etifoxine is directed tocompounds of Formula IA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof,wherein: each X¹, X², X³, X⁴, X⁵ and X⁶ are independently selected fromhydrogen and deuterium.

In embodiments, in such compounds of Formula IA, each X¹ is deuterium.

In embodiments, the compounds of Formula IA have each X¹ is hydrogen.

In embodiments, X², X³, X⁴, X⁵ and X⁶ are hydrogen such that thedeuterated analog of etifoxine is a compound having the structure ofFormula IIA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In one such embodiment, X¹, X², X³, X⁴, X⁵ and X⁶ are hydrogen such thatthe deuterated analog of etifoxine is a compound having the structure ofFormula IIIA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, the compounds of Formula IA have each X¹ and each X⁶ asdeuterium. In one such embodiment, X², X³, X⁴ and X⁵ are hydrogen suchthat the deuterated analog of etifoxine is a compound having thestructure of Formula IVA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, compounds of Formula IA have each X¹ and each X⁵ aredeuterium. In one such embodiment, X², X³, X⁴ and X⁶ are hydrogen suchthat the deuterated analog of etifoxine is a compound having thestructure of Formula VA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, compounds of Formula IA have each X¹, X², X³, X⁴, and X⁶are deuterium. In one such embodiment, X⁵ and X⁶ are hydrogen such thatthe deuterated analog of etifoxine is a compound having the structure ofFormula VIA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, compounds of Formula IA have each and X¹, X⁵, and X⁶ aredeuterium. In one such embodiment, X², X³ and X⁴ are hydrogen such thatthe deuterated analog of etifoxine is a compound having the structure ofFormula VIIA:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, the compound is directed to compounds of Formula IB:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof,wherein: each of X¹, X² and X³ are independently selected from hydrogenand deuterium. In one embodiment, in such compounds each X¹ isdeuterium.

In embodiments, each X² and X³ are hydrogen such that the deuteratedanalog of etifoxine is a structure of Formula IIB below:

and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments the deuterated analog of etifoxine is6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine andpharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments the deuterated analog of etifoxine is6-chloro-N-(ethyl-d5)-4-methyl-4-(phenyl-d5)-4H-3,1-benzoxazin-2-amineand pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments the deuterated analog of etifoxine is6-chloro-N-(ethyl-d5)-4-(methyl-d3)-4-(phenyl-d5)-4H-3,1-benzoxazin-2-amineand pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments the deuterated analog of etifoxine is6-chloro-V-(ethyl-1,1-d2)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amineand pharmaceutically acceptable salts, solvates, and prodrugs thereof.

In embodiments, a compound of Formulae I-II described hereinabove and6-chloro-N-(ethyl-ds)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine;6-chloro-N-(ethyl-d5)-4-methyl-4-(phenyl-d5)-4H-3,1-benzoxazin-2-amine;6-chloro-N-(ethyl-d5)-4-(methyl-d3)-4-(phenyl-d5)-4H-3,1-benzoxazin-2-amine;or 6-chloro-V-(ethyl-1,1-d2)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine has an isotopic enrichment factor for eachdesignated deuterium atom of at least 3500 (52.5% deuteriumincorporation at each designated deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium), at least 5500 (82.5% deuteriumincorporation), at least 6000 (90% deuterium incorporation), at least6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuteriumincorporation), at least 6533 (98% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

In embodiments, the compounds of Formulae I-II described hereinabove,are enantiomerically pure deuterated S-etifoxine isomer, In thecompositions provided herein, deuterated enantiomerically pureS-etifoxine analog or a pharmaceutically acceptable salt, solvate, orprodrug thereof can be present with other active or inactiveingredients. For example, a pharmaceutical composition comprisingdeuterated enantiomerically pure S-etifoxine analog can comprise, forexample, about 90% excipient and about 10% enantiomerically puredeuterated S-etifoxine analog. In certain embodiments, theenantiomerically pure S-etifoxine deuterated analog in such compositionscan, for example, comprise, at least about 99.9% by weight S-etifoxinedeuterated analog and at most about 0.1% by weight R-etifoxinedeuterated analog. In embodiments, the active ingredient can beformulated with little or no excipient or carrier.

In one aspect, the compounds of Formulae I-II described hereinabove, areenantiomerically pure deuterated R-etifoxine isomer. In the compositionsprovided herein, deuterated enantiomerically pure R-etifoxine analog ora pharmaceutically acceptable salt, solvate, or prodrug thereof can bepresent with other active or inactive ingredients. For example, apharmaceutical composition comprising deuterated enantiomerically pureR-etifoxine analog can comprise, for example, about 90% excipient andabout 10% enantiomerically pure deuterated R-etifoxine analog. Inembodiments, the enantiomerically pure R-etifoxine deuterated analog insuch compositions can, for example, comprise, at least about 99.9% byweight R-etifoxine deuterated analog and at most about 0.1% by weightR-etifoxine deuterated analog. In embodiments, the active ingredient canbe formulated with little or no excipient or carrier.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering etifoxine to apatient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering R-etifoxine toa patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering anenantiomerically pure R-etifoxine to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering S-etifoxine toa patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering anenantiomerically pure S-etifoxine to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of etifoxine to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of R-etifoxine to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of an enantiomerically pure R-etifoxine to a patient in needthereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of S-etifoxine to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of an enantiomerically pure S-etifoxine to a patient in needthereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering a deuteratedanalog of etifoxine as depicted in any of the Formulae describedhereinabove to a patient in need thereof.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering an etifoxine,a deuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, or prodrug thereof to a patient in need thereof in an amount ofabout 0.1 mg to about 2000 mg. In embodiments, the methods of treating adevelopmental disorder and/or seizure disorder include administering atleast one etifoxine selected from R-etifoxine, S-etifoxine, andcombinations thereof in an amount of about 0.1 mg to about 2000 mg. Inembodiments, methods of treating a developmental disorder and/or aseizure disorder include administering at least one deuterated analog ofetifoxine selected from Formulas I-VII described herein and combinationthereof in an amount of about 0.1 mg to about 2000 mg. In embodiments,methods of treating a developmental disorder and/or a seizure disorderinclude administering at least one deuterated analog of etifoxineselected from deuterated R-etifoxine, deuterated S-etifoxine, andcombinations thereof in an amount of about 0.1 mg to about 2000 mg.

In embodiments, an etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof isadministered to a patient in an amount which is effective (an “effectiveamount”) to provide improvement in one or more symptoms of thedevelopmental and/or seizure disorders mentioned above. In embodiments,methods of treating a developmental and/or seizure disorder describedherein include administering an etifoxine, a deuterated analog ofetifoxine, or a pharmaceutically acceptable salt, solvate, or prodrugthereof to a patient in need thereof in an amount which is effective toprovide improvement in next day functioning of the patient.

In embodiments, the amount of an etifoxine, a deuterated analog ofetifoxine, or a pharmaceutically acceptable salt, solvate, or prodrugthereof administered daily can be between about 10 mg and 1000 mg ormore. For example, the daily dosage can be 10 mg, 15 mg, 20 mg, 25 mg,50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg,500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg,725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg,950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg,1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg,1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg,1550 mg, 1575 mg or 1600 mg. In general, the daily dosage should notexceed 1600 mg. However, there are situations when amounts greater than1600 mg can be administered. In embodiments, an adult dose can be about300-400 mg per day and can be increased to 600 mg per day. Dosages canbe lower for infants and children than for adults. In embodiments, apediatric dose can be about 10-500 mg per day in 3 to 4 divided doses.

In embodiments, an etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof can beadministered one, two, three, four or more times daily in divided doses.In embodiments, an etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof isadministered via a pharmaceutical composition. Pharmaceuticalcompositions herein encompass dosage forms. Dosage forms hereinencompass unit doses. In embodiments, as discussed below, various dosageforms including conventional formulations and modified releaseformulations can be administered one or more times daily. Any suitableroute of administration may be utilized, e.g., oral, rectal, nasal,pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial,intramuscular, intraperitoneal and subcutaneous routes. Suitable dosageforms include tablets, capsules, oral liquids, powders, aerosols,transdermal modalities such as topical liquids, patches, creams andointments, parenteral formulations and suppositories. In embodiments,rectal suppositories containing an etifoxine, a deuterated analog ofetifoxine, or a pharmaceutically acceptable salt, solvate, or prodrugthereof can be administered in a dose range of about 450-600 mg per dayin adults and about 10-400 mg per day in infants and children.Etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof may be administeredintravenously to adults, infants and children, e.g., to treatdevelopmental disorders and/or seizure disorders. In embodiments, unitdoses in connection with any route of administration can include 0.005mg, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, 9.75mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg,450 mg, 475 mg or 500 mg an etifoxine, a deuterated analog of etifoxine,or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Inembodiments, such amounts may be administered one or more times daily.

In embodiments, etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof can beformulated in oral capsules or tablets comprising about 15 mg, about 25mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg,about 150 mg, about 175 mg, about 200 mg, about 250 mg or about 300 mgof the active ingredient.

In embodiments, R-etifoxine and/or S-etifoxine can be formulated in oralcapsules or tablets comprising about 15 mg, about 25 mg, about 40 mg,about 50 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg,about 175 mg, about 200 mg, about 250 mg or about 300 mg of the activeingredient.

In embodiments, deuterated etifoxine, deuterated R-etifoxine, and/ordeuterated S-etifoxine can be formulated in oral capsules or tabletscomprising about 15 mg, about 25 mg, about 40 mg, about 50 mg, about 75mg, about 100 mg, about 120 mg, about 150 mg, about 175 mg, about 200mg, about 250 mg or about 300 mg of the active ingredient.

In embodiments, methods of treating a developmental disorder and/or aseizure disorder are provided which include administering to a patientin need thereof a pharmaceutical composition including etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, or prodrug thereof wherein the composition provides improvementin one or more symptoms of the disorder for more than 6 hours afteradministration to the patient. In embodiments, methods of treating adevelopmental disorder and/or a seizure disorder are provided whichinclude administering to a patient in need thereof a pharmaceuticalcomposition including etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof whereinthe composition provides improvement in one or more symptoms of thedisorder for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours afteradministration to the patient. In embodiments, the pharmaceuticalcompositions provide improvement of next day functioning of the patient.For example, the pharmaceutical compositions may provide improvement inone or more symptoms of the disorder for more than about, e.g., 2 hours,4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18hours, 20 hours, 22 hours or 24 hours after administration and wakingfrom a night of sleep.

In embodiments, methods include treating a developmental disorder and/ora seizure disorder by administering to a subject in need thereof atleast one compound selected from the group consisting of etifoxine,R-etifoxine, S-etifoxine, deuterated etifoxine, deuterated R-etifoxine,deuterated S-etifoxine, combinations thereof, and pharmaceuticallyacceptable salts, solvates, hydrates, or prodrugs thereof.

In embodiments, methods include treating a developmental disorder and/ora seizure disorder by administering to a subject in need thereof about0.05 mg to about 1500 mg of a compound selected from the groupconsisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof. Inembodiments, methods include treating a developmental disorder and/or aseizure disorder by administering to a subject in need thereof about0.07 mg to about 1000 mg of a compound selected from the groupconsisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof. Inembodiments, the amount of a compound selected from the group consistingof etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof can be between 0.001 and1500 mg/day, or 0.05 mg/kg/day to 500 mg/kg/day, for treatment of adevelopmental disorder and/or a seizure disorder. For example, the dailydosage can be, e.g., in the range of about 0.05 to 1500 mg, 0.05 to 1250mg, 0.05 to 1000 mg, 0.05 to 750 mg, 0.05 to 500 mg, 0.05 to 450 mg,0.05 to 300 mg, 0.05 to 250 mg, 0.05 to 200 mg, 0.05 to 175 mg, 0.05 to150 mg, 0.05 to 125 mg, 0.05 to 100 mg, 0.05 to 75 mg, 0.05 to 50 mg,0.05 to 30 mg, 0.05 to 25 mg, 0.05 to 20 mg, 0.05 to 15 mg, 0.05 to 10mg, 0.05 to 5 mg, 0.05 to 1mg, 0.1 to 1500 mg, 0.1 to 1250 mg, 0.1 to1000 mg, 0.1 to 750 mg, 0.1 to 500 mg, 0.1 to 450 mg, 0.1 to 300 mg, 0.1to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg, 0.1 to 150 mg, 0.1 to 125 mg,0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 25 mg,0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 0.5to 1500 mg, 0.5 to 1250 mg, 0.5 to 1000 mg, 0.5 to 750 mg, 0.5 to 500mg, 0.5 to 450 mg, 0.5 to 300 mg, 0.5 to 250 mg, 0.5 to 200 mg, 0.5 to175 mg, 0.5 to 150 mg, 0.5 to 125 mg, 0.5 to 100 mg, 0.5 to 75 mg, 0.5to 50 mg, 0.5 to 30 mg, 0.5 to 25 mg, 0.5 to 20 mg, 0.5 to 15 mg, 0.5 to10 mg, 0.5 to 5 mg, 0.5 to 1 mg, 1 to 1500 mg, 1 to 1000 mg, 1 to 500mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 175 mg, 1 to 150 mg, 1to 125 mg, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 to 25 mg,1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 1500 mg, 5 to 1000mg, 5 to 500 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175 mg, 5to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg,5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 1500 mg, 10 to1000 mg, 10 to 500 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to175 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 1500 mg,15 to 1000 mg, 15 to 500 mg, 15 to 300 mg, 15 to 250 mg, 15 to 200 mg,15 to 175 mg, 15 to 150 mg, 15 to 125 mg, 15 to 100 mg, 15 to 75 mg, 15to 50 mg, 15 to 30 mg, 15 to 25 mg, 15 to 20 mg, 20 to 1500 mg, 20 to1000 mg, 20 to 500 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to175 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20 to 75 mg, 20 to 50mg, 20 to 30 mg, 20 to 25 mg, 25 to 1500 mg, 25 to 1000 mg, 25 to 500mg, 25 to 300 mg, 25 to 250 mg, 25 to 200 mg, 25 to 175 mg, 25 to 150mg, 25 to 125 mg, 25 to 100 mg, 25 to 75 mg, 25 to 50 mg, 25 to 30 mg,30 to 1500 mg, 30 to 1000 mg, 30 to 500 mg, 30 to 300 mg, 30 to 250 mg,30 to 200 mg, 30 to 175 mg, 30 to 150 mg, 30 to 125 mg, 30 to 100 mg, 30to 75 mg, 30 to 50 mg, 35 to 1500 mg, 35 to 1000 mg, 35 to 500 mg, 35 to300 mg, 35 to 250 mg, 35 to 200 mg, 35 to 175 mg, 35 to 150 mg, 35 to125 mg, 35 to 100 mg, 35 to 75 mg, 35 to 50 mg, 40 to 1500 mg, 40 to1000 mg, 40 to 500 mg, 40 to 300 mg, 40 to 250 mg, 40 to 200 mg, 40 to175 mg, 40 to 150 mg, 40 to 125 mg, 40 to 100 mg, 40 to 75 mg, 40 to 50mg, 50 to 1500 mg, 50 to 1000 mg, 50 to 500 mg, 50 to 300 mg, 50 to 250mg, 50 to 200 mg, 50 to 175 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100mg, 50 to 75 mg, 75 to 1500 mg, 75 to 1000 mg, 75 to 500 mg, 75 to 300mg, 75 to 250 mg, 75 to 200 mg, 75 to 175 mg, 75 to 150 mg, 75 to 125mg, 75 to 100 mg, 100 to 1500 mg, 100 to 1000 mg, 100 to 500 mg, 100 to300 mg, 100 to 250 mg, 100 to 200 mg, 100 to 175 mg, 100 to 150 mg, 100to 125 mg, 125 to 1500 mg, 125 to 1000 mg, 125 to 500 mg, 125 to 300 mg,125 to 250 mg, 125 to 200 mg, 125 to 175 mg, 125 to 150 mg, 150 to 1500mg, 150 to 1000 mg, 150 to 500 mg, 150 to 300 mg, 150 to 250 mg, 150 to200 mg, 150 to 175 mg, 175 to 1500 mg, 175 to 1000 mg, 175 to 500 mg,175 to 300 mg, 175 to 250 mg, 175 to 200 mg, 200 to 1500 mg, 200 to 1000mg, 200 to 500 mg, 200 to 300 mg, 200 to 250 mg, 250 to 1500 mg, 250 to1000 mg, 250 to 500 mg, 250 to 300 mg, 7.5 to 15 mg, 2.5 to 5 mg, 1 to 5mg, with doses of, e.g., about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg,1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg,7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg,30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg and 500 mg beingexamples.

Suitable dosages may be administered to a subject having a developmentaldisorder and/or a seizure disorder once, twice, three or four timesdaily, every other day, once weekly, or once a month. In embodiments, atleast one compound selected from the group consisting of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, or prodrug thereof is administered to a subject having adevelopmental disorder and/or a seizure disorder twice a day, (e.g.,morning and evening), or three times a day (e.g., at breakfast, lunch,and dinner), at a dose of 1-50 mg/administration. In embodiments, acompound selected from the group consisting of etifoxine, a deuteratedanalog of etifoxine, or a pharmaceutically acceptable salt, solvate, orprodrug thereof is administered to a subject having a developmentaldisorder and/or a seizure disorder 600 mg/per day, 550 mg/per day, 500mg/per day, 450 mg/per day, 400 mg/per day, 350 mg/per day, 300 mg/perday, 250 mg/per day, 240 mg/per day, 230 mg/per day, 225 mg/per day, 220mg/per day, 210 mg/per day, 200 mg/per day, 190 mg/per day, 180 mg/perday, 170 mg/per day, 160 mg/per day, 150 mg/per day, 140 mg/per day, 130mg/per day, 120 mg/per day, 110 mg/per day, 100 mg/per day, 95 mg/perday, 90 mg/per day, 85 mg/per day, 80 mg/per day, 75 mg/per day, 70mg/per day, 65 mg/per day, 60 mg/per day, 55 mg/per day, 50 mg/per day,45 mg/per day, 40 mg/per day, 35 mg/per day, 30 mg/per day, 25 mg/perday, 20 mg/per day, 15 mg/per day, 10 mg/per day, 5 mg/per day, 4 mg/perday, 3 mg/per day, 3 mg/per day, 2 mg/per day, 1 mg/per day, in one ormore doses. In embodiments, an adult dose can be about 0.05 to 500 mgper day and can be increased to 750 mg per day. Dosages can be lower forinfants and children than for adults. In embodiments, an infant orpediatric dose can be about 0.1 to 50 mg per day once or in 2, 3 or 4divided doses. In embodiments, a pediatric dose can be 0.75 mg/kg/day to1.5 mg/kg/day. In embodiments, the subject may be started at a low doseand the dosage is escalated over time.

In embodiments, provided herein are methods of treating a seizuredisorder including administering to a subject in need thereof apharmaceutical composition including at least one compound selected fromthe group consisting of etifoxine, a deuterated analog of etifoxine, ora pharmaceutically acceptable salt, solvate, or prodrug thereof, after awarning sign of an impending seizure is detected to reduce or preventseizure activity.

An effective amount or therapeutically effective amount can be a dosagesufficient to treat, inhibit, or alleviate one or more symptoms of adevelopmental disorder and/or seizure disorder such as reducing thefrequency or severity of seizures, reducing behavior abnormalities (orotherwise improving behavior); or to provide a desired pharmacologicand/or physiologic effect, for example, reducing, inhibiting, orreversing one or more of the underlying pathophysiological mechanismsunderlying the neurological dysfunction, increasing dopamine levels orsignaling, or a combination thereof. The precise dosage will varyaccording to a variety of factors such as subject-dependent variables(e.g., age, immune system health, clinical symptoms etc.). Inembodiments, a subject may be started at a low dose and the dosage isescalated. In this manner, it can be determined if the drug is welltolerated in the subject. Dosages can be lower for children than foradults.

In embodiments, the methods described herein are effective to reduce,delay, or prevent one or more other clinical symptoms of a developmentaldisorder such as Fragile X syndrome or a seizure disorder, such as acuterepetitive seizures. For example, the effect of etifoxine, R-etifoxine,S-etifoxine, deuterated etifoxine, deuterated R-etifoxine, deuteratedS-etifoxine, combinations thereof, pharmaceutically acceptable saltsthereof, derivative or analogue thereof, on a particular symptom,pharmacologic, or physiologic indicator can be compared to an untreatedsubject, or the condition of the subject prior to treatment. Inembodiments, the symptom, pharmacologic, and/or physiologic indicator ismeasured in a subject prior to treatment, and again one or more timesafter treatment is initiated. In embodiments, the control is a referencelevel, or average determined based on measuring the symptom,pharmacologic, or physiologic indicator in one or more subjects that donot have the disease or condition to be treated (e.g., healthysubjects). In embodiments, the effect of the treatment is compared to aconventional treatment that is known the art.

In embodiments, the pharmaceutical compositions described herein may beadministered once daily, twice daily, three times daily, four timesdaily, or every other day. In embodiments, the pharmaceuticalcompositions described herein may be administered by continuousinfusion. In embodiments, a pharmaceutical composition described hereinis provided to the subject in the morning. In embodiments, apharmaceutical composition described herein is provided to the subjectin the evening. In embodiments, a pharmaceutical composition describedherein is provided to the subject once in the evening and once in themorning. In embodiments, a pharmaceutical composition described hereinis provided to the subject once in the morning, once in the afternoonand once in the evening.

Suitable methods of administration include, in addition to the infusionmethods described above, oral, buccal, sublingual, rectal, topical,intranasal, vaginal, parenteral, combinations thereof, and the like.

In embodiments, as mentioned previously, pharmaceutical compositionsherein may be provided with conventional release or modified releaseprofiles. Pharmaceutical compositions may be prepared using apharmaceutically acceptable “carrier” composed of materials that areconsidered safe and effective. The “carrier” includes all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients. The term “carrier” includes, but is notlimited to, diluents, binders, lubricants, disintegrants, fillers, andcoating compositions. Those with skill in the art are familiar with suchpharmaceutical carriers and methods of compounding pharmaceuticalcompositions using such carriers.

In embodiments, pharmaceutical compositions herein are modified releasedosage forms which provide modified release profiles. Modified releaseprofiles may exhibit immediate release, delayed release, or extendedrelease profiles. Conventional (or unmodified) release oral dosage formssuch as tablets, capsules, suppositories, syrups, solutions andsuspensions typically release medications into the mouth, stomach orintestines as the tablet, capsule shell or suppository dissolves, or, inthe case of syrups, solutions and suspensions, when they are swallowed.The pattern of drug release from modified release (MR) dosage forms isdeliberately changed from that of a conventional dosage form to achievea desired therapeutic objective and/or better patient compliance. Typesof MR drug products include orally disintegrating dosage forms (ODDFs)which provide immediate release, extended release dosage forms, delayedrelease dosage forms (e.g., enteric coated), and pulsatile releasedosage forms.

An ODDF is a solid dosage form containing a medicinal substance oractive ingredient which disintegrates rapidly, usually within a matterof seconds when placed upon the tongue. The disintegration time forODDFs generally range from one or two seconds to about a minute. ODDFsare designed to disintegrate or dissolve rapidly on contact with saliva.This mode of administration can be beneficial to people who may haveproblems swallowing tablets whether it be from physical infirmity orpsychiatric in nature. Subjects with seizure disorders may exhibit suchbehavior. ODDF's can provide rapid delivery of medication to the bloodstream through mucosa resulting in a rapid onset of action. Examples ofODDFs include orally disintegrating tablets, capsules and rapidlydissolving films and wafers.

Extended release dosage forms (ERDFs) have extended release profiles andare those that allow a reduction in dosing frequency as compared to thatpresented by a conventional dosage form, e.g., a solution or unmodifiedrelease dosage form. ERDFs provide a sustained duration of action of adrug. Suitable formulations which provide extended release profiles arewithin the purview of those skilled in the art. For example, coated slowrelease beads or granules (“beads” and “granules” are usedinterchangeably herein) in which at least one compound selected from thegroup consisting of etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof, isapplied to beads, e.g., confectioners nonpareil beads, and then coatedwith conventional release retarding materials such as waxes, entericcoatings and the like. In embodiments, beads can be formed in which atleast one compound selected from the group consisting of etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, or prodrug thereof is mixed with a material to provide a massfrom which the drug leaches out. In embodiments, the beads may beengineered to provide different rates of release by varyingcharacteristics of the coating or mass, e.g., thickness, porosity, usingdifferent materials, etc. Beads having different rates of release may becombined into a single dosage form to provide variable or continuousrelease. The beads can be contained in capsules or compressed intotablets.

In embodiments, modified dosage forms herein incorporate delayed releasedosage forms having delayed release profiles. Delayed release dosageforms can include delayed release tablets or delayed release capsules. Adelayed release tablet is a solid dosage form which releases a drug (ordrugs) such as etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof, at a timeother than promptly after administration. A delayed release capsule is asolid dosage form in which the drug is enclosed within either a hard orsoft soluble container made from a suitable form of gelatin, and whichreleases a drug (or drugs) at a time other than promptly afteradministration. For example, enteric-coated tablets, capsules, particlesand beads are well-known examples of delayed release dosage forms.Enteric coated tablets, capsules and particles and beads pass throughthe stomach and release the drug in the intestine. In embodiments, adelayed release tablet is a solid dosage form containing a conglomerateof medicinal particles that releases a drug (or drugs) at a time otherthan promptly after administration. In embodiments, the conglomerate ofmedicinal particles are covered with a coating which delays release ofthe drug. In embodiments, a delayed release capsule is a solid dosageform containing a conglomerate of medicinal particles that releases adrug (or drugs) at a time other than promptly after administration. Inembodiments, the conglomerate of medicinal particles are covered with acoating which delays release of the drug.

Delayed release dosage forms are within the purview of those skilled inthe art. For example, coated delayed release beads or granules in whichetifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, is applied to beads, e.g.,confectioners nonpareil beads, and then coated with conventional releasedelaying materials such as waxes, enteric coatings and the like. Inembodiments, beads can be formed in which etifoxine, a deuterated analogof etifoxine, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, is mixed with a material to provide a mass from which the drugleaches out. In embodiments, the beads may be engineered to providedifferent rates of release by varying characteristics of the coating ormass, e.g., thickness, porosity, using different materials, etc. Inembodiments, enteric coated granules of etifoxine, a deuterated analogof etifoxine, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, can be contained in an enterically coated capsule or tabletwhich releases the granules in the small intestine. In embodiments, thegranules have a coating which remains intact until the coated granulesreach at least the ileum and thereafter provide a delayed release of thedrug in the colon. Suitable enteric coating materials are well known inthe art, e.g., EUDRAGIT® coatings such methacrylic acid and methylmethacrylate polymers and others. The granules can be contained incapsules or compressed into tablets.

In embodiments, etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof, isincorporated into porous inert carriers that provide delayed releaseprofiles. In embodiments, the porous inert carriers incorporate channelsor passages from which the drug diffuses into surrounding fluids. Inembodiments, etifoxine, a deuterated analog of etifoxine, or apharmaceutically acceptable salt, solvate, or prodrug thereof, isincorporated into an ion-exchange resin to provide a delayed releaseprofile. Delayed action may result from a predetermined rate of releaseof the drug from the resin when the drug-resin complex contactsgastrointestinal fluids and the ionic constituents dissolved therein. Inembodiments, membranes are utilized to control rate of release from drugcontaining reservoirs. In embodiments, liquid preparations may also beutilized to provide a delayed release profile. For example, a liquidpreparation consisting of solid particles dispersed throughout a liquidphase in which the particles are not soluble. The suspension isformulated to allow at least a reduction in dosing frequency as comparedto that drug presented as a conventional dosage form (e.g., as asolution or a prompt drug-releasing, conventional solid dosage form).For example, a suspension of ion-exchange resin constituents ormicrobeads.

In embodiments, pharmaceutical compositions described herein aresuitable for parenteral administration, including, e.g., intramuscular(i.m.), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.),or intrathecal (i.t.). Parenteral compositions must be sterile foradministration by injection, infusion or implantation into the body andmay be packaged in either single-dose or multi-dose containers. Inembodiments, liquid pharmaceutical compositions for parenteraladministration to a subject include an active substance, e.g.,etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, in any of the respectiveamounts described above. In embodiments, the pharmaceutical compositionsfor parenteral administration are formulated as a total volume of about,e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. Inembodiments, the compositions are contained in a bag, a glass vial, aplastic vial, or a bottle.

In embodiments, pharmaceutical compositions for parenteraladministration are provided wherein the pharmaceutical compositionremains soluble. In embodiments, pharmaceutical compositions forparenteral administration are provided that are stable, soluble, localsite compatible and/or ready-to-use. In embodiments, the pharmaceuticalcompositions herein are ready-to-use for direct administration to asubject in need thereof.

The pharmaceutical compositions for parenteral administration providedherein may include one or more excipients, e,g. solvents, solubilityenhancers, suspending agents, buffering agents, isotonicity agents,stabilizers or antimicrobial preservatives. When used, the excipients ofthe parenteral compositions will not adversely affect the stability,bioavailability, safety, and/or efficacy of (etifoxine, a deuteratedanalog of etifoxine, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, used in the composition. Thus, parenteral compositionsare provided wherein there is no incompatibility between any of thecomponents of the dosage form.

In embodiments, parenteral compositions including etifoxine, adeuterated analog of etifoxine, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, include a stabilizing amount of at leastone excipient. For example, excipients may be selected from the groupconsisting of buffering agents, solubilizing agents, tonicity agents,antioxidants, chelating agents, antimicrobial agents, and preservative.One skilled in the art will appreciate that an excipient may have morethan one function and be classified in one or more defined group.

In embodiments, parenteral compositions include etifoxine, a deuteratedanalog of etifoxine, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, and an excipient wherein the excipient is present at aweight percent (w/v) of less than about, e.g., 10%, 5%, 2.5%, 1%, or0.5%. In embodiments, the excipient is present at a weight percentbetween about, e.g., 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%,0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In embodiments,the excipient is present at a weight percent between about, e.g., 0.001%to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

In embodiments, parenteral compositions may be administered as needed,e.g., once, twice, thrice or four or more times daily, or continuouslydepending on the subject's needs.

In embodiments, parenteral compositions of an active substance, e.g.,(etifoxine, a deuterated analog of etifoxine, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, are provided, wherein thepH of the composition is between about 4.0 to about 8.0. In embodiments,the pH of the compositions is between, e.g., about 5.0 to about 8.0,about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pHof the compositions is between, e.g., about 6.5 to about 7.5, about 7.0to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. Inembodiments, the pH of the aqueous solution is, e.g., about 6.8, about7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0,about 8.2, about 8.4, or about 8.6.

In embodiments, the etifoxines described herein can be administered incombination with one or more additional active ingredients, such asother agents effective for CNS disorders or mental disorders. Suchagents include, but are not limited to the following: serotonin receptor(e.g., 5-HT1A) agonists and antagonists; neurokinin receptor antagonistsor corticotropin releasing factor receptor (CRF1) antagonists; melatoninreceptor agonists; and nicotinic agonists, muscarinic agents,acetylcholinesterase inhibitors and dopamine receptor agonists. Incertain embodiments, the other active agents are arylpiperazines, forexample buspirone, gepirone, ipsapirone and tondospirone; benzodiazepinederivatives such as alprazolam, bromazepam, camazepam, chlordiazepoxide,clobazam, clorazepate, chotiazepam, cloxazolam, diazepam, ethylloflazepate, etizolam, fluidazepam, flutazolam, flutoprazepam,halazepam, ketazolam, lorazepam, loxapine, medazepam, metaclazepam,mexazolam, nordazepam, oxazepam, oxazolam, pinazepam, prazepam andtofisopam; carbamates such as cyclarbamate, emylcamate,hydroxyphenamate, meprobamate, phenprobamate and tybamate; and otherssuch as alpidem, benzoctamine, captodiamine, chlormezanone, flesinoxan,fluoresone, glutamic acid, hydroxyzine, lesopitron, mecloralurea,mephenoxalone, mirtazepine, oxanamide, phenaglycodol, suriclone andzatosetron.

In embodiments, the other additional active agent is fluoxetine(Prozac®), paroxetine (Paxil®), sertraline (Zoloft®), citalopram(Celexa®) orfluvoxamine (Luvox®), venlafaxine (Effexor®), mirtazapine(Remeron®), nefazodone (Serzone®), trazodone (Desyrel®), venlafaxine(Effexor®), bupropion (Wellbutrin®), lithium (Eskalith, Lithobid®),valproate (Depakene®, Depakote®) carbamazepine (Epitol, Tegretol®),neurontin (Gabapentin®), lamictal (Lamotrigine®), ziprasidone (Geodon®),risperidone (Risperdal®), quetiapine (Seroquel®), phenelzine (Nardil®),tranylcypromine (Parnate®), amitriptyline (Elavil®), protriptyline(Vivactil®), desipramine (Norpramin®), nortriptyline (Aventyl®,Pamelor®), trimipramine (Surmontil®), perphenazine (Triavil®),maprotiline (Ludiomil®), mirtazapine (Remeron®), methylphenidate(Ritalin®) or dextroamphetamine (Dexedrine®).

In embodiments, the other additional active agent is an antidepressant,such as a tricyclic antidepressant (“TCA”), a selective serotoninreuptake inhibitor (“SSRI”), a serotonin and noradrenaline reuptakeinhibitor (“SNRI”), a dopamine reuptake inhibitor (“DRI”), anoradrenaline reuptake inhibitor (“NRI”), a dopamine and noradrenalinereuptake inhibitor (“DNRI”), a monoamine oxidase inhibitor (“MAOI”), analpha-2-receptor blocker or another antidepressant.

Exemplary TCAs include, but are not limited to, amitriptyline (Elavil®),amoxapine (Asendin®), clomipramine (Anafranil®), desipramine(Norpramin®), doxepin (Adapin®, Sinequan®), imipramine (Tofranil®),maprotiline (Ludiomil®), nortriptyline (Aventyl®, Pamelor®),protriptyline (Vivactil®) and trimipramine (Surmontil®).

Exemplary SSRIs include, but are not limited to, sertraline (Zoloft®),sertraline metabolite demethylsertraline, fluoxetine (Prozac®),norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine (Luvox®),paroxetine (Seroxat®, Paxil®) and its alternative formulation,Paxil-CR®, citalopram (Celexa®), citalopram metabolitedesmethylcitalopram, escitalopram (Lexapro®), d,1-fenfluramine(Pondimin®), femoxetine, ifoxetine, cyanodothiepin, litoxetine,cericlamine and dapoxetine.

Exemplary NRIs include, but are not limited to, reboxetine (Edronax®)and all isomers of reboxetine, i.e., (R/R,S/S,R/S,S/R), desipramine(Norpramin®), maprotiline (Ludiomil®), lofepramine (Gamanil®),oxaprotiline, fezolamine, atomoxetine (Strattera®), nomifensine(Merital®), viloxazine (Vivalan®), or mianserin (Bolvidon®).

Exemplary SNRIs include, but are not limited to, venlafaxine (Effexor®),venlafaxine metabolite O-desmethylvenlafaxine, clomipramine(Anafranil®), clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran, imipramine (Tofranil® or Janimine®) andnefazaodone (Serzone®).

Exemplary MAOIs include, but are not limited to, phenelzine (Nardil®),tranylcypromine (Parnate®), isocarboxazid (Marplan®) and selegiline(Emsam®, Eldepryl®).

Exemplary alpha-2-receptor blockers include, but are not limited to,mirtazapine (Remeron®, Remeron Soltab®).

Other useful antidepressants include buproprion (Wellbutrin®, Zyban®),buproprion metabolite hydroxybuproprion and trazodone (Desyrel®).

In embodiments, the additional active agent is gaboxadol.

In embodiments, the additional active agent is an allosteric modulator.Allosteric modulators may include a neurosteroid, e.g., ganaxolone orallopregnanolone, a benzodiazepine, e.g., midazolam, clobazam,clonazepam, diazepam, lorazepam, flurazepam, lorazepam etc., or apotassium channel opener, e.g., retigabine or flupirtine.

In embodiments the additional active agent is:

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosure herein belongs.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, up to 10%, up to 5%, and/or up to 1% of a givenvalue. Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, preferablywithin 5-fold, and more preferably within 2-fold, of a value.

“Improvement” refers to the treatment of developmental disorders and/orseizure disorders such as epilepsy, epilepsy with generalizedtonic-clonic seizures, epilepsy with myoclonic absences, frontal lobeepilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen'ssyndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder, infantilespasms (West syndrome), juvenile myoclonic epilepsy (JME),vaccine-related encephalopathy, intractable childhood epilepsy (ICE),Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5disorder, childhood absence epilepsy, essential tremor, acute repetitiveseizures, benign rolandic epilepsy, status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus (SRSE), PCDH19pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawalinduced seizures, increased seizure activity or breakthrough seizures(also called serial or cluster seizures), measured relative to at leastone symptom of the foregoing disorders.

“Improvement in next day functioning” or “wherein there is improvementin next day functioning” refers to improvement after waking from anovernight sleep period wherein the beneficial effect of administrationof the etofixines described herein applies to at least one symptom of asyndrome or disorder herein and is discernable, either subjectively by asubject or objectively by an observer, for a period of time, e.g., 2hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc.after waking.

“Treating”, “treatment” or “treat” can refer to the following:alleviating or delaying the appearance of clinical symptoms of a diseaseor condition in a subject that may be afflicted with or predisposed tothe disease or condition, but does not yet experience or displayclinical or subclinical symptoms of the disease or condition. In certainembodiments, “treating”, “treat” or “treatment” may refer to preventingthe appearance of clinical symptoms of a disease or condition in asubject that may be afflicted with or predisposed to the disease orcondition, but does not yet experience or display clinical orsubclinical symptoms of the disease or condition. “Treating”, “treat” or“treatment” also refers to inhibiting the disease or condition, e.g.,arresting or reducing its development or at least one clinical orsubclinical symptom thereof. “Treating”, “treat” or “treatment” furtherrefers to relieving the disease or condition, e.g., causing regressionof the disease or condition or at least one of its clinical orsubclinical symptoms. The benefit to a subject to be treated may bestatistically significant, mathematically significant, or at leastperceptible to the subject and/or the physician. Nonetheless,prophylactic (preventive) and therapeutic (curative) treatment are twoseparate embodiments of the disclosure herein.

“Pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”, e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In embodiments, this term refers to molecularentities and compositions approved by a regulatory agency of the federalor a state government, as the GRAS list under section 204(s) and 409 ofthe Federal Food, Drug and Cosmetic Act, that is subject to premarketreview and approval by the FDA or similar lists, the U.S. Pharmacopeiaor another generally recognized pharmacopeia for use in animals, andmore particularly in humans.

“Effective amount” or “therapeutically effective amount”, previouslyreferred to, can also mean a dosage sufficient to alleviate one or moresymptoms of a syndrome, disorder, disease, or condition being treated,or to otherwise provide a desired pharmacological and/or physiologiceffect. “Effective amount” or “therapeutically effective amount” may beused interchangeably herein.

“Co-administered with”, “administered in combination with”, “acombination of” or “administered along with” may be used interchangeablyand mean that two or more agents are administered in the course oftherapy. The agents may be administered together at the same time orseparately in spaced apart intervals. The agents may be administered ina single dosage form or in separate dosage forms.

“Subject in need thereof” may include individuals that have beendiagnosed with a developmental disorder and/or seizure disorder such asAngelman syndrome, Fragile X syndrome, epilepsy, epilepsy withgeneralized tonic-clonic seizures, epilepsy with myoclonic absences,frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome,Rasmussen's syndrome, Dravet syndrome, Doose syndrome, CDKL5 disorder,infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME),vaccine-related encephalopathy, intractable childhood epilepsy (ICE),Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5disorder, childhood absence epilepsy, essential tremor, acute repetitiveseizures, benign rolandic epilepsy, status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus (SRSE), PCDH19pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawalinduced seizures, increased seizure activity or breakthrough seizures(also called serial or cluster seizures). The methods may be provided toany individual including, e.g., wherein the subject is a neonate,infant, a pediatric subject (6 months to 12 years), an adolescentsubject (age 12-18 years) or an adult (over 18 years). Subjects includemammals.

“Prodrug” refers to a pharmacological substance (drug) that isadministered to a subject in an inactive (or significantly less active)form. Once administered, the prodrug is metabolized in the body (invivo) into a compound having the desired pharmacological activity.

“Analog” and “Derivative” may be used interchangeably and refer to acompound that possesses the same core as the parent compound, but maydiffer from the parent compound in bond order, the absence or presenceof one or more atoms and/or groups of atoms, and combinations thereof.Enantiomers are examples of derivatives. The derivative can differ fromthe parent compound, for example, in one or more substituents present onthe core, which may include one or more atoms, functional groups, orsubstructures. In general, a derivative can be imagined to be formed, atleast theoretically, from the parent compound via chemical and/orphysical processes.

The term “pharmaceutically acceptable salt”, as used herein, refers toderivatives of the compounds defined herein, wherein the parent compoundis modified by making acid or base salts thereof. Example ofpharmaceutically acceptable salts include, but are not limited to,nontoxic base addition salts with inorganic bases. Suitable inorganicbases such as alkali and alkaline earth metal bases include metalliccations such as sodium, potassium, magnesium, calcium and the like. Thepharmaceutically acceptable salts can be synthesized from the parentcompound by conventional chemical methods.

It should be understood that the examples and embodiments providedherein are exemplary examples embodiments. Those skilled in the art willenvision various modifications of the examples and embodiments that areconsistent with the scope of the disclosure herein. Such modificationsare intended to be encompassed by the claims.

1. A method of treating autism comprising administering to a patient in need thereof, a therapeutically effective dosage of etifoxine or a pharmaceutically acceptable salt thereof, wherein the method provides improvement in one or more symptoms of autism in the patient and the improvement is provided for at least 12 hours after administration.
 2. (canceled)
 3. The method of claim 1, wherein the etifoxine comprises R-etifoxine or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1, wherein the etifoxine is pure R-etifoxine or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1, wherein the etifoxine comprises S-etifoxine or a pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein the etifoxine is pure S-etifoxine or a pharmaceutically acceptable salt thereof.
 7. (canceled)
 8. The method of claim 1, wherein the patient is administered a dosage of between 1 to 75 mg.
 9. The method of claim 1, wherein the patient is administered a dosage of between 1 to 50 mg.
 10. The method of claim 1, wherein the patient is administered a dosage of between 1 to 25 mg.
 11. The method of claim 1, wherein the patient is administered the dosage twice daily.
 12. The method of claim 8, wherein the patient is administered the dosage twice daily. 